This Project will utilize newly discovered protein regulators to locally control the activity of host osteoclasts as a strategy for optimizing the rate and extent of osseointegration of bone onlays and implants in the craniofacial skeleton. An essential goal in the bioengineering design of had tissue implant materials is to achieve rapid mechanical union and stable osseointegration with bone surfaces in the patient. True osseointegration of pure or coated titanium implants is well established in the literature. However, for the repair of large, critical-size defects with particulate hydroxyapatite, treated bone powders, and mineralized rigid implant (eg., Interpore, Bio-Oss, cadaver bone) the typical result is a limited osseointegration (by osteoinduction and/or osteoconduction) at the interface with host bone. Initially, the robust wound-healing reaction reaction at the implant interface is caused by the rich mixture of implant surfaces. Yet these "bioimplants" often remain barren and unossified throughout their bulk, causing long-term problems of resorptive loss and failure. The Project is guided by a central Hypothesis: regulated, non- Inflammatory osteoclastic resorption within a bone implant can be made to play a key role in facilitating its osseointegration through two parallel mechanism-- 1) coupled endothelial cell ingrowth providing new blood vessels, and 2) coupled osteoblastic formation of new bone. The Project will test the role of newly discovered protein factors which regulate osteoclast recruitment, differentiation, and activity in promoting the osseointegration reaction in craniofacial sites in experimental rats and mice. The first aim is to incorporate pure matrix and regulatory proteins into mineralized implants and associated controlled-release polymer coating to Establish reliable set points for high, intermediate, and low osteoclast activity. These factors include specific osteoclast attachment and activating factors (vitronectin, bone sialoprotein, osteopontin, osteocalcin), differentiation factors (M-CSF, RANK-L) and inhibitors (osteoprotegerin). The second aim builds on the first by incorporating an endothelial growth factor (bFGF) into the implant in order to quantitatively correlate the extent of osteogenesis and neovascularization with the number of resident osteoclasts. Rigid, mineralized bone substitutes are clinically important to avoid patient morbidity in craniofacial and spinal surgery. New strategies for controlling osteoclast activity in osseous bioimplans shoulld facilitate biological osseointegration and long-term biomechanical functionality, and my be applicable to a wide range of current and future biomaterials.